Antidepressants, Part 1: 100 Years and Counting: Page 3 of 5

Table 3. Additional FDA-approved indications for at least one antidepressant

Table 4. Four steps of the STAR*D algorithm

Pre-FDA antidepressants: if it works, use it

It is hard for today’s prescribers to imagine a time when the FDA did not exist, and drugs were not systematically evaluated for safety and efficacy before they were allowed to be prescribed to patients. It was President Theodore Roosevelt who in 1906 signed the Food and Drug Act into law that evolved into the FDA. By 1930, a skeleton of our current FDA existed, and over the ensuing decades legislation to require that new drug applications provide evidence of efficacy and safety steadily broadened. This culminated in the passage in 1962 of the Kefauver-Harris Amendment to the Food, Drug, and Cosmetic Act, which is the foundation that the FDA is built on. This amendment was in response to the thalidomide crisis in Europe.

Before the first 2 FDA approvals of antidepressants in 1958 and 1959, many drugs and herbs were marketed for the treatment of depression. Frankincense and St. John’s wort have been used for hundreds of years to treat depression. Cocaine, an early ingredient in Coca-Cola, also has antidepressant properties. In 1904 cocaine was removed from the coca leaves used in the production of Coca-Cola, leaving caffeine from the kola nut as the remaining psychoactive ingredient. Benzedrine (amphetamine) was marketed for narcolepsy and depression starting in 1935. Opioids were also often a preferred drug to treat depression. In 1938 ECT was first used to treat severe depression, and it remains the gold standard with an approximate 74% response rate and 50% rate of remission.5 However, the time-intensive nature of ECT, its expense, and the continued stigmatization of ECT as a treatment continue to limit its use.

The monoamine hypothesis: a detective story involving tuberculosis and hypertension

Since it was first proposed in the 1950s, the monoamine hypothesis of depression has dominated medication development and the treatment of depression. As often is the case in medicine, serendipity provided the clues. Reserpine, which was extracted from Rauwolfia serpentina (Indian snakeroot) in 1952, was shown to be an effective antihypertensive medication; it also had been used for hundreds of years to treat “insanity” in India. As a direct result of reserpine’s ability to irreversibly inhibit the vesicular monoamine transporter in the intracellular environment, the free serotonin, norepinephrine, and dopamine present there are unable to be transported into the vesicles of the presynaptic nerve terminals. These monoamine neurotransmitters are easily degraded by the enzymes monoamine oxidase and catechol–O-methyltransferase in the cytoplasm. The resulting deficiency of synaptic norepinephrine lowers blood pressure but increases the likelihood of depression. The synaptic decrease of dopamine improves psychosis but causes pseudoparkinsonism.

In support of the reserpine evidence that monoamines contribute to depression, in 1952, iproniazid (isoniazid with a propyl group attached) was shown to irreversibly inhibit the cytoplasmic enzyme monoamine oxidase, with the resulting effect of increased neuronal levels of serotonin, norepinephrine, and dopamine. Although at that time both isoniazid and iproniazid were being used to treat tuberculosis, physicians observed that patients who received these drugs also demonstrated significant improvements in their mood, appetite, and sense of well-being. In 1952, Robitzek and Selikoff reported:

So accentuated has been the feeling of the sense of well-being, that disciplinary measures have been necessary; the feeling of well-being may be due to a “resurgent animal vigour.” Patients usually feel better before any objective measurements of improvement can be made.6

By 1957 Roland Kuhn had discovered that a drug derived from chlorpromazine, which itself was derived from an antihistamine, had significant antidepressant properties, especially in patients with psychomotor retardation. In collaboration with Geigy Pharmaceutical Company, he developed imipramine (originally known as G22355). Iproniazid was approved by the FDA in 1958, and imipramine was approved in 1959. These 2 drugs became the mechanistic foundation of all of our current antidepressant medications. In 1961, Julius Axelrod, who won a Nobel Prize in 1970, demonstrated that imipramine inhibited the reuptake of norepinephrine in cats. The iconic paper that summarized all of the evidence for monoamine and solidified the modulation of serotonin, norepinephrine, and dopamine in future drug development was published in 1965 by Joseph Schildkraut.7

Mechanism of action: stuck in the monoamine hypothesis paradigm

Despite an information explosion in our understanding of the human brain over the past 50 years, all current FDA-approved antidepressants continue to modulate some aspect of the serotonin, norepinephrine, or dopamine systems. Novel mechanisms of action have been pursued, but none successfully. Unlike in the treatment of psychotic disorders, where clozapine remains the gold standard of antipsychotic medication efficacy, no such gold standard exists for depression. Of the many choices we have, selecting the first-line antidepressant is largely a decision reached after weighing the risks and benefits of each drug with each patient’s presenting symptoms, functional impairment, lethality, past treatment history, preferences, comorbid psychiatric and medical conditions, motivation, and willingness to participate in other effective treatments such as cognitive behavioral or interpersonal psychotherapy (see Table 1).

Taking these patient-specific factors into consideration, a solid understanding of the wide-ranging pharmacokinetic and pharmacodynamic properties of each antidepressant can help inform antidepressant choice. There are basic mechanisms, pathways, and structures that are similar to each of the 3 monoamines targeted. As the MAOIs have shown, elevation of neuronal concentrations of serotonin, norepinephrine, and/or dopamine provides a robust antidepressant response.